The present invention relates to 6-thioxanthines and in particular to 3,8-disubstituted-6-thioxanthines having bronchodilator activity and which are useful in the treatment of chronic obstructive airway disease.
Brit. J. Pharmacol., 1961, 17, 196-207 describes 3-isobutyl-6-thioxanthine. This compound (compound no. 30 in Table 4) was tested, along with 6-thiotheophyllines (1,3-disubstituted-6-thioxanthines), 6-thiotheobromines (3,7-disubstituted-6-thioxanthines) and 6-thiocaffeines (1,3,7-trisubstituted-6-thioxanthines), for bronchodilator activity. The authors concluded, from these experiments, that only 6-thiotheophyllines were of any potential therapeutic interest.
European patent publication No. 191313A (equivalent to U.S. Pat. No. 4,710,503) describes certain 6-thioxanthines having bronchodilator activity in which the 3-nitrogen is substituted by an ethyl, n-propyl or n-butyl group, whilst the 8-carbon is either unsubstituted or substituted by a methyl or ethyl group. The preferred materials are said to be 3-ethyl-6-thioxanthine and 3-n-propyl-6-thioxanthine.
It has now been found that 6-thioxanthines in which both the 3 and the 8 positions are substituted by alkyl, cycloalkyl or cycloalkylalkyl groups exhibit greater bronchodilator activity than 6-thioxanthines in which only the 3 position is substituted.
U.S. Pat. No. 4,546,182 describes 3,8-dialkylxanthines and their bronchodilator activity. The present inventors have also found that the replacement of the 6-oxo group, of the compounds described in U.S. Pat. No. 4,546,182, with a 6-thio group, enhances bronchodilator activity.
It is an object of the present invention to provide 3,8-disubstituted-6-thioxanthines which have an enhanced bronchodilator effect.
Other objects and advantages of the present invention will become apparent from the following detailed description thereof.
According to the present invention, there is provided a 6-thioxanthine of formula I or a pharamaceutically acceptable salt thereof ##STR2## wherein R.sub.3 is a C.sub.2 to C.sub.6 alkyl, a C.sub.3 to C.sub.7 cycloalkyl group or a C.sub.4 to C.sub.8 cycloalkylalkyl group, and R.sub.8 is a C.sub.1 to C.sub.6 alkyl, a C.sub.3 to C.sub.7 cycloalkyl group or a C.sub.4 to C.sub.8 cycloalkylalkyl group provided that when R.sub.3 is an ethyl, n-propyl or n-butyl group, R.sub.8 is a C.sub.3 to C.sub.6 alkyl, a C.sub.3 to C.sub.7 cycloalkyl group or a C.sub.4 to C.sub.8 cycloalkylalkyl group.
Preferably R.sub.3 is a C.sub.2 to C.sub.5 alkyl, a C.sub.3 to C.sub.5 cycloalkyl or a C.sub.4 -C.sub.6 cycloalkylalkyl group and R.sub.8 is a C.sub.2 to C.sub.5 alkyl or C.sub.3 to C.sub.5 cycloalkyl group. Preferably R.sub.3 and R.sub.8, when combined contain between 5 and 8 carbon atoms.
Thus R.sub.3 may be a hexyl, methylpentyl, dimethylbutyl or ethylbutyl group, but is preferably an ethyl, propyl, cyclopropyl, butyl, cyclobutyl, cyclopropylmethyl, pentyl, cyclopentyl, methylbutyl, or dimethylpropyl group, whilst R.sub.8 may be methyl, hexyl, methylpentyl, dimethylbutyl or ethylbutyl group but is preferably an ethyl, propyl, cyclopropyl, butyl, cyclobutyl, pentyl, cyclopentyl, methylbutyl or dimethylpropyl group.
In a particular preferred embodiment of the present invention, R.sub.3 is an ethyl, n-propyl, isopropyl, isobutyl, secondary butyl, cyclopropylmethyl, n-pentyl, 2-methylbutyl, 3-methylbutyl or 2,2-dimethylpropyl group and R.sub.8 is an ethyl, isopropyl, cyclopropyl, n-butyl, isobutyl, t-butyl, cyclobutyl or n-pentyl group.
Especially preferred compounds have R.sub.3 as ethyl, n-propyl or isopropyl and R.sub.8 as isopropyl, cyclopropyl or cyclobutyl.
The compounds of the present invention have increased bronchodilator activity when compared with both
(i) the equivalent xanthine, (oxygen replaces sulphur), and PA1 (ii) the 3-substituted-6-thioxanthine obtained by replacing the 8-alkyl, cycloalkyl or cycloalkylalkyl group of a compound according to this invention by a hydrogen atom. PA1 (a) Binders, such as cellulose and its derivatives, starches, polyvinylpyrrolidone, natural gums, gelatin, PA1 (b) Glidants, such as talc and fumed silica, PA1 (c) Lubricants, such as stearate salts, PEG waxes, PA1 (d) Disintegrants, such as starch and its derivatives, microcrystalline cellulose, croscarmellose sodium, low substituted hydroxypropyl cellulose, cross linked polyvinylpyrrolidone, PA1 (e) Diluents, such as sugars and sugar alcohols, PA1 (f) Colourants, Flavourants and Sweeteners.
Thus 3-n-propyl-8-cyclobutyl-6-thioxanthine has an enhanced bronchodilator effect compared with both 3-n-propyl-8-cyclobutylxanthine and 3-n-propyl-6-thioxanthine.
Certain of these novel 6-thioxanthines may also exhibit other therapeutic activities, for example anti-inflammatory activity.
The present invention includes pharmaceutically acceptable salts of compounds of formula I with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" means salts, the cations of which are relatively innocuous to the animal organism when used in therapeutic doses so that the beneficial pharmacological properties of the parent compounds of formula I are not impaired by side effects ascribable to the cations. Suitable salts include alkali metal salts, e.g. sodium and potassium, ammonium salts and amine salts, such as glycine, lysine, ethylene diamine, choline, diethanolamine, triethanolamine, octadecylamine, diethylamine, triethylamine, 1-amino-2-propanol, 2-amino-2-(hydroxymethyl)-propane-1,3-diol and 1-(3,4-dihydroxyphenyl)-2-isopropyl-aminoethanol.
According to a further aspect of the present invention there is provided a pharmaceutical composition for use in the treatment of chronic obstructive airway disease, comprising a 6-thioxanthine of formula I or a pharmaceutically acceptable salt thereof wherein R.sub.3 and R.sub.8 are as hereinbefore defined in conjunction with a pharmaceutically acceptable diluent of carrier.
In such compositions, the present thioxanthines may be the sole active ingredient. Alternatively, they may be combined with such drug substances as beta-agonists (e.g. salbutamol, terbutaline, rimiterol and fenoterol), calcium ion antagonists (e.g. nifedipine, verapamil and diltiazem), and mucolytic agents (e.g. ambroxol and bromhexine).
In clinical practice, the compounds of the present invention may be administered rectally, nasally, sublingually, by injection, by inhalation or, which is preferred, orally. The compounds may be administered as pharmaceutical compositions in solid, semi-solid, liquid or capsule form. Usually the active ingredient will comprise between 0.1 and 99% (by wt) of the pharmaceutical composition, especially between 0.5 and 20% (by wt) for compositions intended for injection and between 0.1 and 50% (by wt) for compositions intended for oral administration.
Solid, oral dosage forms according to this invention may be prepared by combining the active ingredient with excipients and diluents such as
Advantageously, the solid, oral dosage form may have a protective coating which may, for example, serve to mask the taste of the active ingredient.
In addition to the above materials, in a further aspect of the present invention, the pharmaceutical composition may also contain substances suitable for the formation of a controlled release formulation. In particular, the composition may contain a hydrated, water soluble, hydroxyalkyl cellulose, especially hydroxyethyl cellulose, and a higher aliphatic alcohol, especially cetostearyl alcohol, as described in British Patent No. 1405088 (equivalent to U.S. Pat. Nos. 3,965,256 and 4,235,870), the contents of which documents are herein incorporated by way of reference.
Soft gelatin capsules consisting of gelatin and, for example, glycerol as a plasticiser, may contain the active ingredient in an oil, such as sesame oil, olive oil or arachis oil, or admixed with a PEG wax. Hard gelatin capsules may contain granules of the active ingredient mixed with suitable excipients and diluents.
Liquid, oral dosage forms may be elixirs, syrups or suspensions. Such forms may contain sweeteners, flavourants, preservatives, emulsifying agents and dispersing agents.
Parenteral forms may be an aqueous solution or suspension of the active ingredient, optionally containing stabilizing agents and/or buffer substances.
For inhalation purposes, the active ingredient may be delivered via an aerosol or a nebuliser. The active ingredient may be present as a solid, a suspension or a solution.
The dosage of the present 6-thioxanthines that will be administered to a patient will vary within wide limits and will depend on various factors such as the type of patient and the disease to be treated. A suitable oral dosage may be 25 to 500 mg given 1 to 4 times a day, while a suitable parenteral dose may be 10 to 250 mg also given 1 to 4 times per day.
The compounds of general formula I may be prepared by thionation of the corresponding 6-oxo compounds. This may be performed, for example, by treatment of the 6-oxo compounds with phosphorus pentasulphide in pyridine. This thionation is suitably carried out by treating a suspension of the 6-oxo compound in pyridine with a molar excess of phosphorus pentasulphide (e.g. from 1.25 to 2.00 moles of P.sub.2 S.sub.5 per mole of 6-oxo compound).
The starting 6-oxo compounds may be prepared from 4,5-diamino-3-substituted pyrimidine-2,6-diones in the manner described in U.S. Pat. No. 4,546,182. Alternatively they may be prepared by other standard acylation procedures followed by ring closure in alkaline solution.
6-Thioxanthines according to this invention, methods of preparing such thioxanthines and pharmaceutical compositions containing such thioxanthines will now be described by way of example only.